EP1807112B1 - Stable aqueous formulation of a platin derivative - Google Patents

Stable aqueous formulation of a platin derivative Download PDF

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EP1807112B1
EP1807112B1 EP05801421A EP05801421A EP1807112B1 EP 1807112 B1 EP1807112 B1 EP 1807112B1 EP 05801421 A EP05801421 A EP 05801421A EP 05801421 A EP05801421 A EP 05801421A EP 1807112 B1 EP1807112 B1 EP 1807112B1
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oxaliplatin
solution
stable aqueous
acetate
aqueous formulation
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EP1807112A1 (en
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Reinhard Rametsteiner
Heinz Schnait
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Ebewe Pharma GmbH Nfg KG
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—Compounds containing heavy metals
    • A61K31/282—Platinum compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • the invention relates to stable aqueous formulations of a platinum derivative, in particular of oxaliplatin, and to their pharmaceutical use as medicaments.
  • Oxaliplatin is an antineoplastic agent derived from the US 4,169,846 is known. Oxaliplatin is used alone or in combination with 5-FU and folinate primarily for the treatment of metastatic colorectal cancer and preferably administered parenterally.
  • WO 03/047587 A is a formulation of oxaliplatin with an effective stabilizing amount of lactic acid or its salts known.
  • a concentration of 0.001 M to 0.0005 M of stabilizer is used to prepare the formulation.
  • formulations of oxaliplatin containing a buffering additive selected from oxalic acid or an alkali metal salt of oxalic acid are known.
  • the stabilizing effect of oxalic acid or alkali metal salts of oxalic acid is contrasted with the use of other customary buffer substances.
  • Citrate, sodium acetate, tris, glycine and phosphate in each case in a concentration of 0.1 M are used as customary buffer substances.
  • the object of the invention was to provide a stable aqueous formulation of oxaliplatin which has improved stability over the known aqueous formulations.
  • the object has surprisingly been achieved that a stable aqueous formulation of OXaliplatin is obtained by addition of sodium acetate in a very low concentration.
  • the invention therefore relates to a stable aqueous solution of oxaliplatin, characterized in that the aqueous solution has sodium acetate in a concentration of 0.005 to 0.00005 M as a stabilizing additive.
  • Sodium acetate have in the concentration range of 0.005 to 0.00005 M excellent stabilizing effect of the aqueous oxaliplatin solution.
  • the aqueous oxaliplatin solution contains one of the stabilizing additives in a concentration of 0.0001 to 0.001 M.
  • the content of oxaliplatin in the aqueous stable formulation according to the invention may be 0.1-10 mg / ml, preferably 2-5 mg / ml.
  • the stable aqueous formulation preferably has a pH of 4 to 6.
  • the stable aqueous formulations of the invention have after a storage period of 3 months, at 45 ° C and 75% rel. Moisture at least 95% of the original oxaliplatin content.
  • the preparation according to the invention is prepared by dissolving oxaliplatin in water or in an aqueous solution of the stabilizing additive with stirring. If the dissolution in water is the Adding the stabilizing additive as an additional manufacturing step necessary. Subsequently, the pH is adjusted. The solution is finally sterilized by means of a suitable sterilization method and filled into appropriate containers (if appropriate under a protective gas atmosphere). The containers used were previously cleaned and sterilized.
  • the stable aqueous formulations of oxaliplatin according to the invention are intended for parenteral administration as "ready to use” formulations and can be administered after dilution with common infusion media, such as 5% glucose, using conventional instruments.
  • oxaliplatin solutions were prepared with different stabilizing N additives and stored and tested under the conditions described in the following tables.
  • the content and purity were determined by HPLC on an Octadecyl silica 5 ⁇ m column. The evaluation was carried out by means of UV detection at 210 nm and against oxaliplatin as an external standard. A content of 100% corresponds to a concentration of 2 mg / ml oxaliplatin.
  • the sodium acetate used in the present invention shows an excellent stabilizing effect even at a low concentration of 0.0005 M.

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Abstract

Disclosed is a stable aqueous formulation of a platin derivative, particularly oxaliplatin. The selected stabilizing additive is effective even in very small concentrations.

Description

Die Erfindung betrifft stabile wässrige Formulierungen eines Platin Derivats, insbesondere von Oxaliplatin, sowie deren pharmazeutische Anwendung als Arzneimittel.The invention relates to stable aqueous formulations of a platinum derivative, in particular of oxaliplatin, and to their pharmaceutical use as medicaments.

Oxaliplatin ist ein antineoplastischer Wirkstoff, der aus der US 4 169 846 bekannt ist. Oxaliplatin wird alleine oder in Kombination mit 5-FU und Folinat vor allem zur Behandlung von metastasiertem Dickdarm-Mastdarmkrebs eingesetzt und bevorzugt parenteral appliziert.Oxaliplatin is an antineoplastic agent derived from the US 4,169,846 is known. Oxaliplatin is used alone or in combination with 5-FU and folinate primarily for the treatment of metastatic colorectal cancer and preferably administered parenterally.

Aus der EP 774 963 A sind pharmazeutisch stabile Zubereitungen von Oxaliplatin für die parenterale Anwendung bekannt. Die beschriebene Lösung von Oxaliplatin in Wasser weist einen pH-Wert von 4.5 bis 6 auf und soll frei von jedem sauren oder alkalischen Zusatz oder Puffermittel oder anderem Zusatzstoff sein.From the EP 774 963 A Pharmaceutically stable preparations of oxaliplatin are known for parenteral use. The described solution of oxaliplatin in water has a pH of 4.5 to 6 and should be free of any acidic or alkaline additive or buffering agent or other additive.

Aus der WO 03/047587 A ist eine Formulierung von Oxaliplatin mit einer effektiven stabilisierenden Menge Milchsäure bzw. deren Salzen bekannt. Dabei wird in den Beispielen eine Konzentration von 0.001 M bis 0.0005 M an Stabilisierungsmittel zur Herstellung der Formulierung verwendet.From the WO 03/047587 A is a formulation of oxaliplatin with an effective stabilizing amount of lactic acid or its salts known. In the examples, a concentration of 0.001 M to 0.0005 M of stabilizer is used to prepare the formulation.

Aus der EP 943 331 A sind Formulierungen von Oxaliplatin bekannt, die einen Pufferzusatz ausgewählt aus Oxalsäure oder einem Alkalimetallsalz der Oxalsäure enthalten.
Dabei wird die stabilisierende Wirkung von Oxalsäure bzw. Alkalimetallsalzen der Oxalsäure der Verwendung anderer üblicher Puffersubstanzen gegenübergestellt..
Als übliche Puffersubstanzen werden dabei Citrat, Natriumacetat, Tris, Glycin und Phosphat jeweils in einer Konzentration von 0.1 M verwendet.From the EP 943 331 A For example, formulations of oxaliplatin containing a buffering additive selected from oxalic acid or an alkali metal salt of oxalic acid are known.
The stabilizing effect of oxalic acid or alkali metal salts of oxalic acid is contrasted with the use of other customary buffer substances.
Citrate, sodium acetate, tris, glycine and phosphate in each case in a concentration of 0.1 M are used as customary buffer substances.

Aufgabe der Erfindung war es eine stabile wässrige Formulierung von Oxaliplatin bereitzustellen, die gegenüber den bekannten wässrigen Formulierungen eine verbesserte Stabilität aufweisen.The object of the invention was to provide a stable aqueous formulation of oxaliplatin which has improved stability over the known aqueous formulations.

Die Aufgabe konnte überraschenderweise gelöst werden, dass eine stabile wässrige Formulierung von OXaliplatin durch Zugabe von Natriumacetat in einer sehr geringen Konzentration erhalten wird.The object has surprisingly been achieved that a stable aqueous formulation of OXaliplatin is obtained by addition of sodium acetate in a very low concentration.

Gegenstand der Erfindung ist daher eine stabile wässrige Lösung von Oxaliplatin, dadurch gekennzeichnet, dass die wässrige Lösung als stabilisierendes Additiv Natriumacetat in einer Konzentration von 0.005 bis 0.00005 M aufweist.The invention therefore relates to a stable aqueous solution of oxaliplatin, characterized in that the aqueous solution has sodium acetate in a concentration of 0.005 to 0.00005 M as a stabilizing additive.

Natriumacetat weisen im Konzentrationsbereich von 0.005 bis 0.00005 M ausgezeichnete stabilisierende Wirkung der wässrigen Oxaliplatinlösung auf. Bevorzugt enthält die wässrige Oxaliplatinlösung eines der stabilisierenden Additive in einer Konzentration von 0.0001 bis 0.001 M.Sodium acetate have in the concentration range of 0.005 to 0.00005 M excellent stabilizing effect of the aqueous oxaliplatin solution. Preferably, the aqueous oxaliplatin solution contains one of the stabilizing additives in a concentration of 0.0001 to 0.001 M.

Der Gehalt an Oxaliplatin in der erfindungsgemäßen wässrigen stabilen Formulierung kann 0.1 - 10 mg/ml, vorzugsweise 2- 5 mg/ml betragen.The content of oxaliplatin in the aqueous stable formulation according to the invention may be 0.1-10 mg / ml, preferably 2-5 mg / ml.

Bevorzugt weist die stabile wässrige Formulierung einen pH-Wert von 4 bis 6 auf.The stable aqueous formulation preferably has a pH of 4 to 6.

Die erfindungsgemäßen stabilen wässrigen Formulierungen weisen nach einer Lagerzeit von 3 Monaten, bei 45°C und 75 % rel. Feuchtigkeit mindestens 95% des ursprünglichen Gehalts an Oxaliplatin auf.The stable aqueous formulations of the invention have after a storage period of 3 months, at 45 ° C and 75% rel. Moisture at least 95% of the original oxaliplatin content.

Die Herstellung der erfindungsgemäßen Zubereitung erfolgt durch Auflösen von Oxaliplatin in Wasser oder in einer wässrigen Lösung des stabilisierenden Additivs unter Rühren. Erfolgt die Auflösung in Wasser ist die Zugabe des stabilisierenden Additivs als zusätzlicher Herstellungsschritt notwendig. Anschließend erfolgt die Einstellung des pH-Wertes. Die Lösung wird abschließend mittels geeigneter Sterilisationsmethode sterilisiert und in entsprechende Behältnisse abgefüllt (gegebenenfalls unter Schutzgasatmosphäre). Die eingesetzten Behältnisse wurden vorher gereinigt und sterilisiert.The preparation according to the invention is prepared by dissolving oxaliplatin in water or in an aqueous solution of the stabilizing additive with stirring. If the dissolution in water is the Adding the stabilizing additive as an additional manufacturing step necessary. Subsequently, the pH is adjusted. The solution is finally sterilized by means of a suitable sterilization method and filled into appropriate containers (if appropriate under a protective gas atmosphere). The containers used were previously cleaned and sterilized.

Die erfindungsgemäßen stabilen wässrigen Formulierungen von Oxaliplatin sind zur parenteralen Verabreichung als "ready to use" Formulierungen vorgesehen und können nach Verdünnung mit gängigen Infusionsmedien, wie z.B. 5 % Glukose mit Hilfe herkömmlicher Instrumente verabreicht werden.The stable aqueous formulations of oxaliplatin according to the invention are intended for parenteral administration as "ready to use" formulations and can be administered after dilution with common infusion media, such as 5% glucose, using conventional instruments.

Beispiele:Examples: Vergleichsbeispiel 1: Lösung mit PhosphatComparative Example 1: Solution with phosphate

40 mg Oxaliplatin werden in einem 20 ml Messkolben mit 1 ml Phosphatlösung (89.1 mg Na2HPO4.2H2O in 50 ml gereinigtem Wasser gelöst; entspricht 0.01 mol/l) versetzt und mit gereinigtem Wasser auf 20 ml aufgefüllt. Anschließend wird der pH-Wert mittels 10% Phosphorsäure auf 5.0 eingestellt. Diese Lösung wird anschließend über einen 0.2 µm Spritzenfilter filtriert, zu je 2 ml in 5 ml Vials abgefüllt, verbördelt und unter den unten angegebenen Bedingungen gelagert.Dissolve 40 mg of oxaliplatin in a 20 ml volumetric flask with 1 ml of phosphate solution (89.1 mg Na 2 HPO 4 .2H 2 O dissolved in 50 ml of purified water equivalent to 0.01 mol / l) and make up to 20 ml with purified water. Subsequently, the pH is adjusted to 5.0 by means of 10% phosphoric acid. This solution is then filtered through a 0.2 micron syringe filter, filled into 2 ml each in 5 ml vials, crimped and stored under the conditions given below.

Vergleichsbeispiel 2: Lösung mit CitratComparative Example 2: Solution with citrate

40 mg Oxaliplatin werden in einem 20 ml Messkolben mit 1 ml Citratlösung (148.0 mg Natriumcitrat.2H2O in 50 ml gereinigtem Wasser gelöst; entspricht 0.01 mol/l) versetzt und mit gereinigtem Wasser auf 20 ml aufgefüllt. Anschließend wird der pH-Wert mittels 10 % Citronensäure auf 5.0 eingestellt. Diese Lösung wird anschließend über einen 0.2 µm Spritzenfilter filtriert, zu je 2 ml in 5 ml Vials abgefüllt, verbördelt und unter den unten angegebenen Bedingungen gelagert.Dissolve 40 mg of oxaliplatin in a 20 ml volumetric flask with 1 ml citrate solution (148.0 mg sodium citrate.2H 2 O dissolved in 50 ml purified water equivalent to 0.01 mol / l) and make up to 20 ml with purified water. Subsequently, the pH is adjusted to 5.0 by means of 10% citric acid. This solution is then filtered through a 0.2 micron syringe filter, filled into 2 ml each in 5 ml vials, crimped and stored under the conditions given below.

Vergleichsbeispiel 3: Lösung mit PhosphatComparative Example 3: Solution with phosphate

40 mg Oxaliplatin werden in einem 20 ml Messkolben mit 1 ml Phosphatlösung (89.1 mg Na2HPO4.2H2O in 50 ml gereinigtem Wasser gelöst; entspricht 0.01 mol/l) versetzt und mit gereinigtem Wasser auf 20 ml aufgefüllt. Anschließend wird der pH-Wert mittels 10 % Phosphorsäure auf 4.0 eingestellt. Diese Lösung wird anschließend über einen 0.2 µm Spritzenfilter filtriert, zu je 2 ml in 5 ml Vials abgefüllt, verbördelt und unter den unten angegebenen Bedingungen gelagert.Dissolve 40 mg of oxaliplatin in a 20 ml volumetric flask with 1 ml of phosphate solution (89.1 mg Na 2 HPO 4 .2H 2 O dissolved in 50 ml of purified water equivalent to 0.01 mol / l) and make up to 20 ml with purified water. Subsequently, the pH is adjusted to 4.0 by means of 10% phosphoric acid. This solution is then filtered through a 0.2 micron syringe filter, filled into 2 ml each in 5 ml vials, crimped and stored under the conditions given below.

Beispiel 1: Lösung mit AcetatExample 1: Solution with acetate

80 ml gereinigtes Wasser werden in einem 100 ml Messkolben vorgelegt. Anschließend werden 0.0042 g Natriumacetat zugesetzt. Man gibt 500 mg Oxaliplatin zur Lösung und rührt die Lösung so lange bis Oxaliplatin vollständig gelöst ist. Anschließend wird der pH Wert mit 1 % Essigsäure auf 5.0 eingestellt. Nach Auffüllen des Messkolbens mit gereinigtem Wasser bis zur Marke wird die Lösung über einen 0.2 µm Spritzenfilter filtriert, zu je 2ml in 5 ml Vials abgefüllt, verbördelt und unter den unten angegebenen Bedingungen gelagert.80 ml of purified water are placed in a 100 ml volumetric flask. Subsequently, 0.0042 g of sodium acetate are added. Add 500 mg of oxaliplatin to the solution and stir the solution until oxaliplatin is completely dissolved. The pH is then adjusted to 5.0 with 1% acetic acid. After filling the volumetric flask with purified water to the mark, the solution is filtered through a 0.2 micron syringe filter, filled into 2 ml each in 5 ml vials, crimped and stored under the conditions given below.

Beispiel 2: Lösung mit AcetatExample 2: Solution with acetate

80 ml gereinigtes Wasser werden in einem 100 ml Messkolben vorgelegt. Anschließend werden 0.0042 g Natriumacetat zugesetzt. Man gibt 500 mg Oxaliplatin zur Lösung und rührt die Lösung so lange bis Oxaliplatin vollständig gelöst ist. Anschließend wird der pH Wert mit 1 % Essigsäure auf 6.0 eingestellt. Nach Auffüllen des Messkolbens mit gereinigtem Wasser bis zur Marke wird die Lösung über einen 0.2 µm Spritzenfilter filtriert, zu je 2ml in 5 ml Vials abgefüllt, verbördelt und unter den unten angegebenen Bedingungen gelagert.80 ml of purified water are placed in a 100 ml volumetric flask. Subsequently, 0.0042 g of sodium acetate are added. Add 500 mg of oxaliplatin to the solution and stir the solution until oxaliplatin is completely dissolved. The pH is then adjusted to 6.0 with 1% acetic acid. After filling the volumetric flask with purified water to the mark, the solution is filtered through a 0.2 micron syringe filter, filled into 2 ml each in 5 ml vials, crimped and stored under the conditions given below.

Analog zu den hier ausgeführten Beispielen wurden Oxaliplatin Lösungen mit unterschiedlichen stabilisierendeN Additiven hergestellt und unter den in den folgenden Tabellen beschriebenen Bedingungen gelagert und getestet.Analogous to the examples set forth herein, oxaliplatin solutions were prepared with different stabilizing N additives and stored and tested under the conditions described in the following tables.

Die Untersuchung des Gehalts und der Reinheit erfolgte mittels HPLC an einer Octadecyl silica 5 µm Säule. Die Auswertung erfolgte mittels UV Detektion bei 210 nm und gegen Oxaliplatin als externer Standard. Ein Gehalt von 100 % entspricht einer Konzentration von 2 mg/ml Oxaliplatin.The content and purity were determined by HPLC on an Octadecyl silica 5 μm column. The evaluation was carried out by means of UV detection at 210 nm and against oxaliplatin as an external standard. A content of 100% corresponds to a concentration of 2 mg / ml oxaliplatin.

Die Ergebnisse sind in den Tabellen 1-2 dargestellt Tab.1 Gehalt und Reinheit nach 4 Wochen Lagerung bei 40°C/75.r.F. Gehalt
Ausgang Gehalt
40°C / 4Wochen 0,5mM Citronensäure 99.1% 97.1% 0,5mM Na-Acetat 101.7% 99.9% 0,5mM Weinsäure 99.7% 97.2% 0,5mM Phosphat 97.6% 96.8% 0,5mM Bernsteinsäure 99.5% 96.1% 0,5mM Maleinsäure 101.8% 98.7% Tab. 2 Gehalt und Reinheit nach 3 Monaten Lagerung bei 40°C175.r.F Gehalt
Ausgang Gehalt
40°C / 3 Monate 0,5mM Na-Acetat 101.7% 99.5% 0,5mM Weinsäure 99.7% 97.5% 0,5mM Bernsteinsäure 99.5% 95.9% 0,5mM Maleinsäure 101.8% 97.3% Tab 3 Gehalt nach 4 Wochen Lagerung bei 40°C/75.r.F
Additiv = Natriumacetat; pH =5.5 Tab. 3a Menge Additiv Gehalt
Ausgang Gehalt
4Wochen 0.05 mM Na-Acetat 100,90% 99,40% 0.1 mM Na-Acetat 99,60% 97,90% 0.5 mM Na-Acetat 101,70% 99,90% 1 mM Na-Acetat 101,20% 99,10% 5 mM Na-Acetat 100,30% 98,20% ohne Additiv 101,80% 95,90% Gehalt und Reinheit nach 3 und 6 Monaten bei 25°C/60%.r.F
Additiv = Natriumacetat; pH = 5.5 Tab. 3b Menge Additiv Gehalt
Ausgang Gehalt
3 Monate Gehalt
6 Monate 0.5 mM Na-Acetat 100,10% 99,60% 99,50% The results are shown in Tables 1-2 <b> Tab.1 Content and purity after 4 weeks of storage at 40 ° C / 75.rF </ b> salary
output salary
40 ° C / 4 weeks 0.5mM citric acid 99.1% 97.1% 0.5mM Na-acetate 101.7% 99.9% 0.5mM tartaric acid 99.7% 97.2% 0.5mM phosphate 97.6% 96.8% 0.5mM succinic acid 99.5% 96.1% 0.5mM maleic acid 101.8% 98.7% salary
output salary
40 ° C / 3 months 0.5mM Na-acetate 101.7% 99.5% 0.5mM tartaric acid 99.7% 97.5% 0.5mM succinic acid 99.5% 95.9% 0.5mM maleic acid 101.8% 97.3% Content after 4 weeks storage at 40 ° C / 75.rF
Additive = sodium acetate; pH = 5.5 Tab. 3a Amount of additive salary
output salary
4 weeks 0.05 mM Na acetate 100.90% 99.40% 0.1 mM Na acetate 99.60% 97.90% 0.5 mM Na acetate 101.70% 99.90% 1 mM Na acetate 101.20% 99.10% 5 mM Na acetate 100.30% 98.20% without additive 101.80% 95.90% Content and purity after 3 and 6 months at 25 ° C / 60% .rF
Additive = sodium acetate; pH = 5.5 Tab. 3b Amount of additive salary
output salary
3 months salary
6 months 0.5 mM Na acetate 100.10% 99.60% 99.50%

Wie aus den Tabellen 1-3 hervorgeht, zeigt das erfindungsgemäß eingesetzte Natriumacetat bereits in einer geringen Konzentration von 0.0005 M eine ausgezeichnete stabilisierende Wirkung.As is apparent from Tables 1-3, the sodium acetate used in the present invention shows an excellent stabilizing effect even at a low concentration of 0.0005 M.

Claims (5)

  1. Stable aqueous solution of oxaliplatin, characterized in that the aqueous solution exhibits, as stabilizing additive, sodium acetate in a concentration of 0.005 to 0.00005M.
  2. Stable aqueous solution according to Claim 1, characterized in that the stabilizing additive is present in a concentration of 0.0001 to 0.001M.
  3. Stable aqueous solution of oxaliplatin according to either of Claims 1 and 2, characterized in that the content of oxaliplatin in the solution is 0.1-10 mg/ml.
  4. Stable aqueous solution of oxaliplatin according to Claim 3, characterized in that the content of oxaliplatin in the solution is 2-5 mg/ml.
  5. Stable aqueous solution of oxaliplatin according to one of Claims 1 to 4, characterized in that the solution exhibits a pH value of 4 to 6.
EP05801421A 2004-11-02 2005-10-28 Stable aqueous formulation of a platin derivative Not-in-force EP1807112B1 (en)

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DE102004052877A DE102004052877B4 (en) 2004-11-02 2004-11-02 Stable aqueous formulations of a platinum derivative
PCT/EP2005/011570 WO2006048194A1 (en) 2004-11-02 2005-10-28 Stable aqueous formulation of a platin derivative

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EP1807112B1 true EP1807112B1 (en) 2009-12-09

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US (1) US7812052B2 (en)
EP (1) EP1807112B1 (en)
AT (1) ATE451122T1 (en)
CA (1) CA2585866A1 (en)
DE (2) DE102004052877B4 (en)
WO (1) WO2006048194A1 (en)

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JP5929607B2 (en) * 2012-08-06 2016-06-08 ニプロ株式会社 Oxaliplatin formulation

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US6476068B1 (en) * 2001-12-06 2002-11-05 Pharmacia Italia, S.P.A. Platinum derivative pharmaceutical formulations
DE10314377A1 (en) * 2003-03-28 2004-10-07 Stada Arzneimittel Ag Pharmaceutical composition useful for tumor therapy comprises water, oxaliplatin and an acid other than oxalic acid
WO2005020980A1 (en) * 2003-08-28 2005-03-10 Mayne Pharma Pty Ltd Acid containing oxaliplatin formulations

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CA2585866A1 (en) 2006-05-11
US20070299132A1 (en) 2007-12-27
WO2006048194A1 (en) 2006-05-11
ATE451122T1 (en) 2009-12-15
DE502005008686D1 (en) 2010-01-21
DE102004052877A1 (en) 2006-05-04
EP1807112A1 (en) 2007-07-18
US7812052B2 (en) 2010-10-12
DE102004052877B4 (en) 2008-06-19

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